DPP-IV is a serine protease, which recognizes an amino acid sequence having proline (or alanine or hydroxyproline) the penultimate position from the N-terminal and produces dipeptide Xaa-Pro (Xaa shows an optional amino acid and Pro shows L-proline). DPP-IV is widely distributed in mammalian tissues and is known to be present particularly in blood, kidney, intestinal epithelium and placenta.
While the physiological role of DPP-IV in mammal has not been completely elucidated, its involvement in a broad range of functions of living organisms such as degradation of neuropeptide (see non-patent reference 1), activation of T cell (see non-patent reference 2), adhesion of metastatic tumor cell to endothelium (see non-patent reference 3), invasion of HIV virus into lymphocytes (see non-patent reference 4) and the like is being clarified. Of these, the role of DPP-IV as an enzyme that inactivates glucagon-like peptide (GLP-1), which is a biogenic substance having a strong insulin secretion ability and controls postprandial blood glucose level, has been drawing attention (see non-patent reference 5).
GLP-1 is known to be metabolized in several minutes in a living organism. In the metabolism, that by DPP-IV is particularly important, because DPP-IV quickly cleaves GLP-1 to produce inert GLP-1 (see non-patent reference 6). In addition, it is considered that physiological action of GLP-1 becomes attenuated further because this inert GLP-1 shows an antagonistic action on GLP-1 receptor (see non-patent reference 7). Therefore, a method for suppressing cleavage of GLP-1 by inhibition of DPP-IV is considered to be the most superior approach for reinforcing GLP-1 action. That is, a DPP-IV inhibitor is expected to be a superior treatment method of curing postprandial hyperglycemia without side effects, such as prolonged hypoglycemia and the like, for non insulin-dependent diabetic (type II diabetes) patients.
Patent applications directed to DPP-IV inhibitors have been already filed.
A compound consisting of a natural amino acid and thiazolidine or pyrrolidine is known to show a DPP-IV inhibitory action (see patent reference 1). Besides this reference, compounds consisting of cyclohexylglycines and thiazolidine have been disclosed (see patent reference 2).    patent reference 1: WO99/61431    patent reference 2: WO02/76450    non-patent reference 1: Heymann et al., FEBS Letters, vol. 91, 360-364 (1978).    non-patent reference 2: Schon et al., Biomedica Biochimica Acta., vol. 44, K9-K15 (1985).    non-patent reference 3: Johnson et al., Journal of Cell Biology, vol. 121, 1423-1432 (1993).    non-patent reference 4: Callebaut et al., Science, vol. 262, 2045-2050 (1993).    non-patent reference 5: Deacon et al., Journal of Clinical Endocrinology and Metabolism, vol. 80, 952-957 (1995).    non-patent reference 6: Deacon et al., American Journal of Physiology, vol. 271, E458-E464 (1996).    non-patent reference 7: Knudsen et al., European Journal of Pharmacology, vol. 318, 429-435 (1996).